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Title:
ELECTRICAL STIMULATION APPARATUS
Document Type and Number:
WIPO Patent Application WO/2018/234964
Kind Code:
A1
Abstract:
Object of the invention is an electrical stimulation apparatus comprising means generating electric pulses arranged in sequences having predetermined values of typical parameters, said typical parameters comprising width, duration and frequency of said pulses, a plurality of stimulation channels, such to deliver said sequences to body regions of an organism in an independent manner, changer means intended to change at least one of said typical parameters such to substantially prevent such organism from getting inured to said electric pulses. The changer means comprise reverser means arranged such to change the pulse polarity.

Inventors:
COMAI, Guido (Via Giuseppe Mazzini 4, Budrio, 40054, IT)
BERTORA, Franco (Via Trento 41/12 A, Genova, 16145, IT)
Application Number:
IB2018/054452
Publication Date:
December 27, 2018
Filing Date:
June 18, 2018
Export Citation:
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Assignee:
FREMSLIFE S.R.L. (Via Pietro Chiesa 9, Genova, 16149, IT)
International Classes:
A61N1/36; A61N1/04; A61N1/32
Domestic Patent References:
WO2017085227A12017-05-26
Foreign References:
US20110054567A12011-03-03
Attorney, Agent or Firm:
KARAGHIOSOFF, Giorgio A. (Via F. Baracca 1/r, Savona, 17100, IT)
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Claims:
CLAIMS

1. Electrical stimulation apparatus, comprising means (14) generating electric pulses arranged in sequences having predetermined values of typical parameters, said typical parameters comprising width, duration and frequency of said pulses, a plurality of stimulation channels (2) , such to deliver said sequences to body regions of an organism in an independent manner, changer means (12, 15, 21, 22) intended to change at least one of said typical parameters such to substantially prevent such organism from getting inured to said electric pulses, characterized in that said changer means comprise reverser means (21, 22) arranged to change the polarity of said pulses.

2. Apparatus according to claim 1 , wherein there is provided a control unit (4) programmed such to control the changer means (12, 15, 21, 22) such to generate electric pulses having width, duration, frequency and polarity settable to generate sequences of pulses comprising sub-sequences of pulses wherein at least one of said width, duration, frequency and polarity parameters is different in at least one preceding or subsequent sub-sequence.

3. Apparatus according to claim 1 or 2 , wherein one or more sub-sequences of reversed polarity pulses are interposed between sub-sequences of non-reversed polarity pulses according to a random order or according to a predetermined and preset and/or adjustable order.

4. Apparatus according to one or more of the preceding claims, wherein the changer means (12, 15, 21, 22) are configured to set successions of pulses having a gradually increasing frequency.

5. Apparatus according to claim , wherein one or more successions of pulses comprises first pulses with a frequency gradually increasing according to a first increment and second pulses with a frequency gradually increasing according to a second increment, said second increment being greater than said first increment .

6. Apparatus according to one or more of the preceding claims, wherein, in use, said pulses are sequentially delivered such to form sequences activating the micro-circulation, said sequences comprising a first sub-sequence (SI) , a second subsequence (S2) and a third sub-sequence (S3) , in said second sub-sequence the polarity of the pulses being changed with respect to said first and said second sub-sequences .

7. Apparatus according to claim 6, wherein in said first sub-sequence and in said third sub- sequence a pulse frequency increment is generated while in said second sub-sequence the duration and/or width of the pulses is changed.

8. Apparatus according to one or more of the preceding claims, wherein the reversed polarity pulses have at least one variable parameter, said parameter being selected from the group consisting of frequency, width and duration.

9. Apparatus according to one or more of the preceding claims , wherein the changer means are configured to change the pulse frequency by steps of 20 Hz.

10. Apparatus according to one or more of the preceding claims , wherein the changer means are configured to change the pulse duration by steps of 10 ps.

11. Apparatus according to one or more of the preceding claims , wherein the changer means are configured to change the pulse width by steps ranging from 0.47 V to 0.63 V, typically 0.5 V.

12. Apparatus according to one or more of the preceding claims, comprising an input unit by means of which the patient is able to act such to change at least one parameter, particularly the polarity of the delivered pulses.

13. Apparatus according to one or more of the preceding claims, wherein there is provided an input voltage for the generating means (14) , said generating means generating sequences of pulses having the same polarity as the input voltage, the changer means comprising a selector able to switch the input voltage for the generating means (14) between two opposite polarity values (VA, VB) such to generate any sequence or sub-sequence of pulses with variable polarity.

14. Electrical stimulation method comprising the generation of a sequence of electric pulses having predetermined values of typical parameters, characterized in that said typical parameters comprise width, duration, frequency and polarity of said pulses, said parameters being settable such to generate sequences of pulses comprising sub-sequences of pulses wherein at least one of said width, duration, frequency and polarity parameters is different in at least one preceding or subsequent sub-sequence .

15. Method according to claim 14, wherein one or more sub-sequences of reversed polarity pulses are interposed between sub-sequences of non-reversed polarity pulses according to a random order or according to a predetermined and preset and/or adjustable order.

Description:
"Electrical stimulation apparatus"

Object of the present invention is an electrical stimulation apparatus.

Clinical data demonstrate that more than one half of the population of western countries is affected by vascular system related diseases, and particularly the cardio-vascular system. In the vascular walls alterations often occur caused by degenerative diseases such as arteriosclerosis which, along with thrombosis, is one of the most frequent causes of obstruction of the peripheral arteries and arteries affecting myocardium and brain.

Arteriosclerosis manifests particularly aggressively and premature in diabetic patients, which are about 3% of the population in Europe and similar percentages of the population in Italy. Such a disease is paralleled by long term complications highly debilitating for the patient, which are due to the degeneration of the larger vessels (macro- angiopathy) , the small vessels (micro-angiopathy) and the peripheral nervous and vegetative system (neuropathy) . Peripheral macro-angiopathy in diabetic patients produces symptoms similar to those observed in non-diabetic patients; however, it manifests prematurely and with higher frequency, and aggravates very rapidly. For the above recited reasons, in the diabetic patients the vascular diseases cause twice the mortality as compared to non-diabetic patients and require long term hospitalizations, with heavy economic and social consequences.

Furthermore, in diabetic patients arteriosclerosis accounts for most of the lower limb amputations (50-70%) , which manifest in such patients with a frequency 5 times higher than the non-diabetic patients. The occlusion of small and medium bore distal arteries under the knee is responsible for the gangrene development. Furthermore, diabetic patients are more frequently suffering from claudicatio intermittens due to calf, thigh or buttock muscle ischemia, than the non-diabetic ones.

In literature some new substances have been recently found and described, which are produced by the endothelial cells, which substances cause the formation of new blood vessels (angiogenesis) and the vasodilation, such as for example the Fibroblast Growth Factor (FGFF) , the Neuronal Growth Factor (NGF) , the Vascular Endothelial Growth Factor (VEGF) .

In order to promote the angiogenesis, VEGF and other angiogenic factors such as FGF can be directly injected in the vascular bed affected by ischaemia and/or occlusion. However the direct injection of VEGF or other angiogenic factors results in a number of drawbacks mainly due to the difficulty of release to all the affected cells. In fact, less than 2% of the injected VEGF effectively takes part to the neo- angiogenesis ; in addition the method is potentially toxic .

Experiments carried out by Kanno et al . demonstrated that by applying a continuous electrical stimulation for 5 days on isolated animal muscles by means of pulses having a width of 0.3 ms , a frequency of 50 Hz and a voltage of 0.1 V, an increase in the VEGF production is observed and the neo-angiogenesis is promoted, by means of an increase of the capillary number and blood flow.

Despite such experiments appear to suggest that the muscle electrical stimulation has beneficial effects on circulation, they do not teach how to apply an electrical stimulation on human beings.

Furthermore, they require a treatment time of several days, which could cause discomforts to the patient due to the excessive length thereof.

It is further known to use the laser transmyocardial revascularization in order to reduce the pain caused by angina; this causes an increase of the VEGF level in myocardium and in endothelial cells of capillaries and arterioles (Lee, SH, Wolf PL, Escudero R, N Eng. J. Med. 2000; 342, 626-33). However, the laser transmyocardial revascularization is an invasive technique leading to limited results.

US 2002/0010492 describes an electrical stimulation device for the controlled production of angiogenic growth factors, by which the VEGF level can be increased, in vitro, by 30-40% with a continuous electrical stimulation having a duration of at least 8 hours.

In this case also, however, long treatment times are required which cause considerable discomforts to the patient.

WO 02/09809 describes an apparatus for the treatment of vascular, or muscular, or tendons diseases, by which a series of electric pulses having a width from 10 to 40 s and an intensity from 100 to 170 uA is applied to a patient. In this way an increase in the VEGF production can be obtained, with subsequent vasodilation and neoangiogenesis .

WO 2004/084988 describes an electrical stimulation apparatus by which, depending on the type of electrical stimulation produced and the configuration parameters adopted, an induced bio- active neuro-modulation can be generated, adapted to produce phenomena of vaso-active type on the microcirculation and the macro-circulation.

These phenomena, in their turn, are mediated by phenomena connected to the direct stimulation of the smooth muscles and by phenomena of the essentially catecholaminergic type, by stimulation of the postsynaptic receptors. The afore mentioned apparatus is able to produce specific stimulation sequences inducing reproducible and constant neurophysiological responses .

Specifically, WO 2004/084988 describes a sequence activating the micro-circulation (ATMC) and a sequence decontracting the muscular fiber (DCTR) , which are able to stimulate different functional contingents, among which the striate muscle, the smooth muscle and the peripheral mixed nerve. The afore mentioned stimulation sequences are assembled on three fundamental parameters: the stimulus duration, the stimulus frequency and the time lags during which different duration/frequency combinations occur in succession. The general operation design of the stimulation sequences reflects the digital-to-analog transduction which occurs in the transmission of a nervous pulse.

The phase and width modulated neuronal electrical stimulation or FREMS ~ (Frequency Rhythmic Electric Modulation described in the afore mentioned WO 2004/084988 and in WO 2004/067087 (incorporated by reference herein) ) , is characterized by the use of transcutaneous electric currents produced by sequential electric pulses having variable frequency and duration. The frequency can change from 0,1 to 999 Hz, the stimulus duration ranges from 0,1 to 40 s and the voltage, constantly hold above perceptive threshold, ranges from 0,1 to 300 V (preferably 150 V) . By suitably combining the afore mentioned frequency and duration changes a specific sequence is obtained, so-called DCTR, having a decontracting effect and comprising a series of substeps, named A, B and C. Frequency and width are constant in the substep A, frequency is constant and width variable in the substep B, frequency is variable and width constant in the substep C.

Experimental studies allowed assessing the effects of FREMS and its ability of evoking composite muscular action potentials (cMAP) , which can be obtained in just the toe adductor muscle by stimulating the posterior tibial nerve, as well as the H reflection amplitude variation by using the latter as a conditioning stimulus. As described in WO 2004/084988, the afore mentioned experimental studies also demonstrated that the cMAP greatest width (0.60 ± 0.02 mV) which can be obtained is about 15 times smaller than the cMAPs obtained with the known devices delivering TENS currents, i.e. widths on the order of 9 ± 0.6 mV with stimuli having a duration typically comprised in a 200-1000 s range. It has been further noticed that the cMAP maximum width value is obtained in presence of a duration/frequency ratio of 0.13 (40ps/29Hz) .

An additional type of sequence, so-called ATCM and conveniently designed to obtain a vaso-active effect, has a prevailing action on the microcirculation motility, i.e. the smooth sphincters of arterioles and venules of the subcutaneous tissue. In practice, as described in WO 2004/084988, a system is obtained which produces a sequence of vasodilations and vasoconstrictions with sequential increases and reductions of blood flow of the micro-circulation surrounding the stimulation area. These vasodilations and vasoconstrictions produce a "pump" effect apparently produced by a neuromodulation of the sympathetic neurovegetative system, which affects the vasodilation just through the smooth muscles of the capillary vessels and arterioles. Thereby it can be highlighted that such a sub-sequence, characterized by alternated rheobase variations, thus produces a vaso-active effect consisting of sequential vasodilation steps and vasoconstriction steps. This indeed also produces a draining effect and, above all, a micro-circulation elasticization and a modulation of the latter around a main leading event which determines its average variation.

One object of the invention is to improve the known electrical stimulation apparatuses.

Another object is to provide an electrical stimulation apparatus which allows stimulating the vascularization and, more generally, the blood flow at injured areas such as to promote the healing of sores or wounds .

The invention achieves the object with an electrical stimulation apparatus, comprising generating means to generate electric pulses arranged in sequences having predetermined values of typical parameters, said typical parameters comprising width, duration and frequency of said pulses, a plurality of stimulation channels, such to independently deliver said sequences to an organism body areas, changer means intended to change at least one of said typical parameters such as to substantially prevent such organism from getting inured to said electric pulses, wherein the changer means further comprise reverser means arranged to change the pulse polarity.

The inventors surprisingly found how the polarity of pulses generated by the FREMS apparatuses is a parameter affecting the vascularization of the areas under treatment, specifically if the known apparatus pulse sequences are modified such to comprise sub-sequences of also reversed polarity pulses .

For this purpose, according to an aspect, the apparatus comprises a control unit programmed to control the changer means such to generate electric pulses having width, duration, frequency and polarity settable to generate pulse sequences comprising pulse sub-sequences, wherein at least one of the afore said width, duration, frequency and polarity parameters is different in at least one preceding or subsequent sub-sequence. Specifically one or more sub-sequences of reversed polarity pulses can be interposed between two or more sub-sequences of non-reversed polarity pulses according to a random order or according to a predetermined and/or preset and/or adjustable order so as to optimize the treatment.

According to another aspect, the invention relates to an electrical stimulation method comprising generating a sequence of electric pulses having predetermined values of typical parameters, wherein said typical parameters comprise width, duration, frequency and polarity of said pulses. The parameters are settable to make pulse sequences comprising pulse sub-sequences wherein at least one of afore said width, duration, frequency and polarity parameters is different in at least one preceding or subsequent sub-sequence.

Specifically, one or more sub-sequences of reversed polarity pulses are interposed among subsequences of non-reversed polarity pulses according to a random order or according to a predetermined and/or preset and/or adjustable order such to obtain the effect.

Further characteristics and refinements are object of the sub-claims.

The characteristics of the invention and the advantages deriving therefrom will be much clearer from the following specification of the accompanying figures, wherein:

Fig. 1 shows a block diagram of an electrical stimulation apparatus according to an embodiment of the invention.

Fig. 2 shows a block diagram of an electrical stimulation apparatus according to another embodiment of the invention.

Fig. 3 shows examples of pulse sub-sequences which can be delivered with the apparatus of the preceding figures.

Fig. 4 shows a table highlighting the substeps of an example of stimulation sequence activating the micro-circulation .

Figure 1 schematically shows the assembly of the circuits comprised in an electrical stimulation apparatus 1, able to produce and deliver FREMS stimulation sequences according to the invention by means of a plurality of independent stimulation channels 2, of which each is formed by a plurality of transcutaneous electrode pairs 7.

In the version of the apparatus 1 shown in figure 1 four stimulation channels 2 are provided, of which only two are depicted (for the sake of clarity) and denoted by 2A, 2B.

In a not depicted version, an apparatus 1 is provided and comprises a number of stimulation channels 2 larger than four.

In another not depicted version, an apparatus 1 is provided and comprises a number of stimulation channels 2 smaller than four.

The apparatus 1 comprises a first control unit 3 and a second control unit 4, mutually interacting and made in the form of microprocessors of known type. The first control unit 3 controls a display device, for example a liquid crystal display 5, and an alphanumerical keyboard 6.

By typing on the latter, a user of the apparatus 1 can direct the operation of the latter and set the parameters, which can be displayed on the display 5, of the electrical stimulations to be delivered to a patient .

In a not depicted version, a device with remote control is provided by which a patient connected to the apparatus 1 can control the operation thereof without interacting with the keyboard 6. This version is particularly useful since it allows the patient to control the apparatus 1 by acting as sensory feedback element with regard to one or more operation unit parameters of the apparatus 1. The first control unit 3 controls a safety switch 9, which in its turn controls an input supply voltage VA. In normal operation conditions, the switch 9 is closed and a voltage adjuster 16 (whose function will be described in the following) comprised in each channel 2 is thus powered. In emergency conditions, for example in case of apparatus malfunction, the first control unit 1 opens the switch 9 and thus interrupts the power to the voltage adjuster 16. To the second control unit 4 a lighting device, for example a LED 10 of known type, is further connected. When a patient is connected to the apparatus 1 by means of the electrodes 7 and the apparatus 1 powered by voltage VA, it delivers an electrical stimulation to the patient, the LED 10 lights up, thus indicating that the patient is subjected to the action of an electric current .

Through a serial communication interface 8 of known type, the first control unit 3 is connected to the second control unit 4, which controls the production of the electric pulses by adjusting the fundamental parameters thereof, i.e. width, duration, frequency and polarity, and comprises an analog-to- digital converter (ADC) 11 and an integrated timing unit (ITU) 12. In the second control unit 4 a medium 20 (depicted by dashed line) can be housed on which the data required for the operation of the apparatus 1, such as, for example, the data related to the stimulation sequences that can be produced by the apparatus 1, are recorded. The medium 20 can be read by data processing means (not depicted) of known type, which are comprised in the apparatus 1 or arranged externally to the apparatus 1 and interfaced with the latter. The data processing means, if comprised in the apparatus 1, can be positioned, for example, in the second control unit 4.

In a not depicted version, the medium 20 is housed in the first control unit 3.

The analog-to-digital converter 11 receives a feedback signal (in the form of a voltage) related to the pulse width, and intervenes by producing a correction and/or a warning signal if the width of the pulse produced by the apparatus 1 is different from the one set by the user. Specifically, the analog-to-digital converter 11 receives a reference voltage V T adjusting the operation of the analog-to- digital converter 11, a further reference voltage VR that allows verifying the proper operation of the analog-to-digital converter 11 and, from each one of the stimulation channels 2, a feedback voltage VF .

The integrated timing unit 12 defines pulse duration and frequency by interacting with a timing control device 13. The latter controls duration and frequency of the produced pulse and, if one and/or the other of these parameters is not correct, it produces and sends a duration error signal ED and/or a frequency error signal EF able to stop the second control unit 4.

Similarly to what described about the first control unit 3, also the second control unit 4 controls safety switches 9 provided in the same number as the number of stimulation channels 2 comprised in the apparatus 1. The safety switches 9 controlled by the first control unit 3 and the second control unit 4 mutually interact and with the LED 10 through an "OR" type logic gate 18.

The electrical signals defining pulse frequency and duration are produced by the integrated timing unit 12 and directly sent to an output pulse generator 14. In the apparatus 1 the output pulse generators 14 are provided in the same number as the number of the stimulation channels 2.

The pulse width is defined and adjusted by a digital-to analog converter (DAC) 15 interacting with the second control unit 4. The digital-to-analog converter 15 produces a plurality of electrical signal defining the pulse width for each single channel 2, and each signal is sent to a voltage adjuster 16. The apparatus 1 comprises the same number of voltage adjusters 16 as the number of stimulation channels 2. From each voltage adjuster 16 an output voltage Vu, whose value ranges from 0 to 300 Volts, is produced and sent to the corresponding output pulse generator 14. Each output pulse generator 14 produces a pulse having predetermined width, frequency and duration, and sends this pulse to a pair of output selectors 17A, 17B, the electrodes 7 being connected thereto. The pairs of output selectors 17A, 17B are provided in the same number as the number of the output pulse generators 14 comprised in the apparatus 1. Each output selector 17A, 17B comprises a plurality of switches 19 provided in the same number as the number of the electrodes 7 connected to the selector, through which the produced pulse can be alternately transmitted to the corresponding electrode 7, or stopped. In each pair of output selectors 17A, 17B the electrodes 7 are functionally combined so as to form four pairs, the electrodes of each pair being respectively denoted as 7A, 7B, 7C e 7D. The electrodes 7 of each pair are connected to the corresponding output selector 17A or 17B.

In a not depicted version, output selectors 17A, 17B comprising a number of pairs of electrodes 7 greater than four are provided.

In another not depicted version, output selectors 17A, 17B comprising a number of pairs of electrodes 7 smaller than four are provided.

When the apparatus 1 is in use it is possible, by acting on the switches 19, to select the electrodes 7 to which the pulse produced by the output pulse generator 14 has to be sent. It is therefore possible to independently use both the pairs of electrodes 7A-7D comprised in two or more stimulation channels 2, and the pairs of electrodes 7A-7D comprised in a single stimulation channel 2.

As shown in Fig. 1, the polarity of the pulses generated by the generator 14 can be reversed by interposing a reverser device 21 driven by the control unit 4 between generator 14 and output selector 17.

A more advanced version provides the possibility of directly acting on the D/A converters 15 such as to provide the adjuster 16 with positive and negative voltage values. This way the pulses getting to the pulse generator 14 already have a set polarity without the need of using additional reverser devices 21.

Alternatively or in combination, as shown in Fig. 2, a second input supply voltage V B , having reversed polarity with respect to V A , and a selector 22 controlled by the control unit 3 or 4 so as to alternately send to the voltage adjuster 16 a voltage with two polarities can be introduced. Thereby, the output voltage to the D/A 15 can remain of a single polarity, the pulse reversion being operated upstream through input voltage selection.

Convenient safety switches 9' driven by the control unit 3 and/or 4 can be serially inserted at the input VB similarly to the switches 9 provided on the input VA and described above.

It has to be observed that figure 2 shows the selector 22 on a single channel for exposition simplicity, but it is obvious that a similar structure can be replicated per each channel so as to independently control the polarity of all the pulses reaching the stimulation electrodes 7.

Whatever the solution adopted is, the apparatus is able to independently control the width, the duration, the frequency and the polarity of the pulses produced by the channels 2 and, thus, to set any typology of stimulation sequence/sub-sequence .

Furthermore, the integrated timing unit 12 allows increasing in a predetermined way the duration of the output pulse. Specifically, it is possible to obtain a percent increase of the duration of an electrical stimulation pulse which is carried out in a plurality of steps, after their completion the pulse duration remains constant.

The percent increase of the pulse duration, the pulse duration and the number of steps are mutually related by the following formula:

Ti (Nf) = To x (1 + I%) Nf

where :

Nf = step number;

Ti (Nf) = Stimulation pulse duration as a function of the step number;

To = Starting stimulation pulse duration;

1% = Pulse duration percent increase.

In the version of the apparatus 1 disclosed in Fig. 1 and 2, the obtainable percent increase 1% is equal to 20%, 25%, 33%, 50%, and the value indicating Nf (i.e., the number of steps) ranges from 0 to 9.

The integrated timing unit 12 further allows the length of the time interval between two subsequent steps to be pseudo-randomly changed. In this way, stimulation sequences can be produced wherein the pulse duration varies proportionally to the percent increase randomly. This allows avoiding biological accommodation phenomena, i.e. the stimulated tissues in a patient can get inured to the pulses and thus become less sensitive to the latter.

In the version of the apparatus 1 depicted in

Fig. 1 and 2, at least four time lags which can be generated by random numbers are provided.

In order to avoid the afore mentioned biological accommodation phenomena, the apparatus 1 can also act by changing the pulse frequency, width and polarity. The frequency, as above described, is adjusted by the integrated timing unit 12, the width is adjusted by the analog-to-digital converter 15 while the polarity is set by the reverser 21, the selector 22 or the digital to analog converter 15.

As above described, a version of the apparatus 1 provided with remote control, by using which the patient can act as a sensory feedback element with respect to the operation of the apparatus 1, is provided. The patient, in fact, can be conveniently trained to change the polarity and/or width during the electrical stimulation treatment, by acting on the digital-to-analog converter 15 by the remote control, such as to avoid the afore mentioned biological accommodation phenomena. For example, the patient can be trained to change the pulse width and/or polarity when the latter reaches a maximum (subjective) tolerability level. Alternatively, the patient can be trained to change the pulse width and/or polarity when the latter reaches the sensitivity threshold.

The pulses generated by the apparatus according to the invention preferably have a width ranging from 1 to 90 ps, a frequency from 0.1 Hz to 1 kHz and a current intensity ranging from 10 to 200 uA. The peak voltage is, in absolute value, above 50 V and can have a range up to 300 V. The changer means are typically set such to change the pulse parameters by discrete steps, for example of 20 Hz as regards frequency, 10 ps as regards duration and variable values ranging from 0.47 V and 0.63 V, typically 0.5 V, as regards width.

More preferably, the afore said pulses have a width ranging from 1 to 49 ps, a frequency from 0.1 Hz to 100 Hz, a current intensity from 10 to 100 uA and a peak voltage from -100 V to +100 V. Even more preferably, the pulse duration ranges from 1 to 40 s , the frequency from 0.1 Hz to 100 Hz and the voltage ranges from -150 V to +150 V.

The electrical stimulation apparatus is configured such to apply a sequence of stimuli comprising a predetermined succession of proper subsequences. Each sub-sequence is the result of the frequency, width, intensity and polarity modulation according to a protocol depending on the desired biochemical effect on cells and tissues. For this purpose the invention also provides a method for delivering pulse sequences according to any possible combination of parameters as described in the following .

In order to obtain micro-circulation activation, a variable polarity sequence of the type shown in figure 4 can be applied. As it can be noticed, after an initial sub-sequence with increasing frequency, in the substep 13 the frequency is abruptly reduced to the 1 Hz value and subsequently increased up to 11 Hz, afterwards it is kept constant for some seconds, so as to cause an effective action on the blood vessels. At this stage, i.e. starting from the substep 38, the frequency value is increased by 10 Hz at each substep, until reaching the 41 Hz value, close to which it has experimentally been verified that the VEGF maximum release is obtained. Such a frequency appears to reasonably be the VEGF resonance frequency.

In order to obtain an even higher VEGF level in blood, the afore said sequence can be repeated several times during the day.

By repeating in succession the same sequence several times in a row, it has been surprisingly observed a synergistic effect, since it has been observed that the result obtained is higher than the sum of the results that would have been logical to expect by applying two sequences independently from one another .

This seems to be due to the polarity change and the abrupt decrease of the frequency of the applied pulses, i.e. the abrupt transition from a relatively high frequency value to the initial 1 Hz value, which introduces a clear demarcation in the applied pulses which translates in a significant energy change. By repeating the sub-sequence several times, an effect similar to the so-called "water hammer" phenomenon, which is known in the hydraulics field, occurs, through which the stimulation by sub-threshold electric pulses allows breaking weak chemical bounds and releasing large amounts of the desired molecules or their transformation, without inducing energy transfer to the tissue.

The frequency change applied is preferably greater than 20 Hz, more preferably greater than 40 Hz and, in some particular cases, can be advantageously greater than 60 Hz .

The pulse polarity can be changed independently from the change of the other parameters, for example randomly so as to increase the vaso-active effect.

With the apparatus according to the invention any typology of sequence can be generated by acting on the changer means .

The changer means can be configured, for example, to set successions of pulses having a gradually increasing frequency. One or more successions of pulses may comprise first pulses with a frequency gradually increasing according to a first increment and second pulses with frequency gradually increasing according to a second increment, said second increment being greater than said first increment.

In an embodiment the apparatus, in use, delivers pulses sequentially so as to form sequences activating the micro-circulation. Said sequences advantageously comprise a first sub-sequence (SI) , a second sub-sequence (S2) and a third sub-sequence (S3) , wherein in said second sub-sequence the polarity of the pulses is changed with respect to said first and said second sub-sequence.

The reversed polarity pulses have at least one variable parameter selected from the group of frequency, width and duration.

In another embodiment, in said first subsequence and in said third sub-sequence a pulse frequency increment is generated while in said second sub-sequence the duration and/or width of the pulses is changed.

In a specific example the sub-sequences SI and S3 are both characterized by a frequency increasing step, with distinct time modes. The sub-sequence S2 is mainly made to produce a variability of the duration of the individual stimuli, in a range of gradually increasing frequencies, so as to reduce the bio-reaction, until stabilizing it. More in detail, the sub-sequence SI comprises steps wherein, after a first adaptation step carried out at 1 Hz frequency, the constant width frequency is gradually increased, thus gradually reducing the bio-reaction. Then, the frequency is increased much more rapidly until reaching a target of 19 Hz. Then the sub-sequence S2 is carried out, which in turn can be divided in four stages termed S2-A, S2-B, S2-C and S2-D, wherein the pulse polarity is reversed. In the sub-sequence S2 , after a step (S2-A) carried out at constant frequency wherein the amplitude is rapidly increased until the moment 1, the frequency is gradually increased, and consequently the bio-reaction rapidly drops until the moment 2 (S2-B) . At this stage the width is reset, rising again to constant frequency until the moment 3 (S2-C) and reversed polarity. Then, the frequency gradually rises again while the width is kept constant and, consequently, the bio-reaction gradually decreases until the moment 3 (S2-D) again reversing the pulse polarity. This way the bio- reaction is discontinuously changed.

Other combinations of parameters , and thus of stimulation sequences with reversed polarity pulses, are of course possible thanks to the great flexibility of the afore described apparatus. For example any one of the sequences described in the afore mentioned document WO2004067087 can be replicated, specifically the sequences described in the tables in figures to be considered integral part of the preset description, changed in the meaning of comprising the further pulse polarity parameter, which parameter can be arbitrarily changed such that positive polarity pulse sequences are interspersed with negative polarity pulse sequences so as to maximize the desired effect, particularly in terms of vascularization and angiogenesis of injured parts.

All without departing from the guiding principle afore described and claimed hereinbelow.